Project Summary Esophageal adenocarcinoma is the most common esophageal malignancy in Western world and the malignancy that is rising the fastest in the United States ? approximately 7% per year over the past 30 years. It has very poor prognosis with less than 15% of patients alive 5 years after diagnosis. Worldwide, 482,300 new esophageal cancer cases and 406,800 deaths occurred in 2008. In order for patients to survive, it is essential to diagnose this malignancy at an early, dysplastic stage. Our group has developed an endoscopic polarized spectroscopic scanning (EPSS) instrument which gives real time in vivo information on the location of invisible high grade dysplasia. This, compatible with existing commercial endoscopes, multispectral imaging instrument is based on the technique of light scattering spectroscopy (LSS), capable of identifying pre-cancer in various epithelial-lined organs, such as esophagus. The EPSS imaging instrument scans the entire esophagus in a matter of minutes providing the physician with real time diagnostic information for guiding biopsy. At the same time, in order to establish unbiased characteristics of the EPSS method and to provide gastroenterologists with accurate quantitative histological and biochemical information needed to visualize invisible dysplasia in esophageal epithelium important technological improvements and additional clinical studies are required. For this competitive renewal program we will build a significantly improved portable EPSS instrument capable of scanning the entire esophagus order of magnitude faster then the existing instrument, depth resolving epithelial structure, and continuously projecting quantitative histological and biochemical as well as diagnostic imaging information on the endoscopy video in real time. Compared to state-of-the-art wide-field techniques, EPSS is distinguished by its ability to locate dysplasia in tissue that shows no visible abnormalities or lesions when observed with white light or fluorescence. By elucidating microscopic subcellular structure with macroscopic spectral measurements, EPSS can locate dysplastic tissue independent of any visual cues. We conclude that EPSS offers great promise for the early detection of dysplasia in Barrett's esophagus. If the EPSS technique were to be used to guide biopsy routinely, unnecessary biopsies would be avoided and focal dysplastic spots would be biopsied that otherwise would be missed.